Background: Pancreatic Ductal Adenocarcinoma (PDA) is among the deadliest of cancers. This project lays out new, subtype-based treatment approaches to PDA. We know that KRAS mutation drives around 90% of PDA, but since we cannot directly inhibit KRAS, we treat PDA with combinations of chemotherapies that are very difficult for patients to tolerate, and leave KRAS unaddressed. Our approach here centers on the use of PDA subtypes that we discovered to guide MEK inhibitor combinations in PDA. We will focus here on the Classical (C)- and Quasi-Mesenchymal (QM)-PDA subtypes, which together represent ~75% of all PDA patients. Rationale: PDA subtypes enable personalized PDA therapy because subtype predicts response to therapy. Furthermore, the mechanism(s) of escape from MEK inhibitors differ by PDA subtype. C-PDA displays robust rebound signaling through receptor tyrosine kinase and atypical protein kinase C signaling. By contrast, we have discovered a new KRAS-driven pathway resulting in the pathological expression of LIF, in the QM-PDA subtype, resulting in elevated and cancer-driving levels of STAT3 signaling. Importantly, both pathways can be targeted, but should be pursued separately in distinct PDA subtypes. Methods: We will use in vivo preclinical PDA models to optimize MEK and ERK inhibitor combinations using distinct, rational combinations for each subtype. In the QM-PDA subtype, we will deplete LIF signaling alongside concurrent gemcitabine treatment. In the C-PDA subtype, we will compare strategies inhibiting protein kinase C with MEK inhibition. Finally, we will also use unbiased methods to interrogate in vivo MEK inhibitor resistance pathways in both subtypes using an innovative, saturating assessment of RAS pathway and microenvironmental interacting pathways in cancer cells, modeled in the intact organism. Expected Results: Results emanating from this R01 will define both the intellectual outline as well as practical, organizing principles to personalize care in PDA. Initiating clinical trials in genomically defined PDA subtypes is an expected deliverable of this grant and understanding MEK inhibitor response and resistance is another. Impact: This project is 100% relevant to pancreatic adenocarcinoma. Our proposal pioneers new approaches to PDA treatment through a use of multiple complementary models of the disease and its prominent subtypes.